Methods and reagents for diagnosis of autoantibodies

ABSTRACT

A number of octapeptides were generated from the sequences encoding the 60 kDa Ro/SSA peptide, the La/SSB autoantigen, the 70 kD nuclear ribonucleoprotein (nRNP), and the Sm B/B′ polypeptide, which represent linear epitopes for autoantibodies present in the sera of SLE and SS patients. These peptides are useful in solid phase assays for patients characterized by the presence of these autoantibodies, and can be used to categorize patients as to the likelihood of developing certain conditions associated with SLE. The peptides are also potentially useful in treatment of these patients using immobilized peptide to remove autoantibody and to block binding of the autoantibodies with patient molecules reactive with the autoantibodies.

This is a divisional of U.S. Ser. No. 07/867,819 filed on Apr. 13, 1992,by John B. Harley for “Methods and Reagents for Diagnosis ofAutoantibodies”, which is a continuation-in-part of U.S. Ser. No.07/648,205 filed Jan. 31, 1991 by John B. Harley for “Assays andTreatments for Autoimmune Diseases” now abandoned, which is acontinuation-in-part of U.S. Ser. No. 07/472,947 entitled ‘Assays andTreatments for Autoimmune Diseases” filed Jan. 31, 1990 by John B.Harley, now abandoned.

The United States government has rights in this invention by virtue ofgrants from the National Institutes of Health AR39577, AI24717, AI21568,AI31584 and AR01844, and the Veteran's Administration.

BACKGROUND OF THE INVENTION

This invention is in the area of the prevention, diagnosis and treatmentof autoimmune diseases, especially systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is similar to many other disorders inwhich autoantibodies are found and thought to be important in etiologyand pathogenesis. SLE can be grouped with those diseases that commonlyhave autoantibodies present but for whom a central role of autoantibodyin pathogenesis leading to clinical expression has yet to be fullyestablished or accepted. Other such diseases include Sjogren's syndrome,rheumatoid arthritis, juvenile onset diabetes mellitus, primary biliarycirrhosis, Wegener's granulomatosis, inflammatory bowel disease, andmany others.

Typically, autoimmune diseases present with a wide array of symptoms andclinical signs. The production of circulating autoantibodies toribonucleoprotein complexes (RNPs) is a unifying characteristic of someof the rheumatic autoimmune diseases. The most common antigens in SLEand closely related disorders include: Ro/SSA, La/SSB, nRNP and Sm.Initially, these antibodies were found using double immunodiffusion, butmore recently sensitive solid phase assays have been developed toquantitate the autoantibodies.

The Ro/SSA RNA-protein particle has been found to be a constituent ofall human cells evaluated to date. Approximately half of Sjogren'ssyndrome (SS) and systemic lupus erythematosus (SLE) patients haveanti-Ro/SSA precipitins. Approximately 75% of patients with subacutecutaneous lupus erythematosus or complement component C2 deficiency withSLE have anti-Ro/SSA precipitins. Over 80% of mothers of newborns withneonatal lupus dermatitis or complete congenital heart block have thisautoantibody. As many as 5% of patients with rheumatoid arthritis,polymyositis, and progressive systemic sclerosis have anti-Ro/SSA, asreported by R. M. Bernstein, et al., Mol. Biol. Med. 2:105-120 (1984);and J. B. Harley and K. K. Gaither, Autoantibodies. In Rheumatic DiseaseClinics of North American: Systemic Lupus Erythematosus 14:1, 43-56.(1988).

Autoantibodies to the La/SSB ribonucleoprotein antigen are also found inpatients with SS and SLE, as reported by Alspaugh, et al., ArthritisRheum. 19:216 (1976) and Mattioli, et al., Arthritis Rheum. 17:421(1974). In addition, these antibodies as reported by Horsfall, et al.,J. Autoimmunity 4:165 (1991), thought to be pathogenic to the fetusduring pregnancy in some mothers who have anti-La/SSB autoantibodies,where they are associated, along with anti-Ro/SSA, with completecongenital heart block (CCHB).

It has been an issue of intensive debate as to whether the manyautoantibodies found in systemic lupus erythematosus and relateddiseases represent an antigen specific or a polyclonal, antigennon-specific response. Evidence that autoantibodies are important in theexpression of SLE and related syndromes is convincing. Specificdepletion in a heart block neonate (Harley, J. B., et al., ArthritisRheum.28:1321-1325 (1985)) and specific anti-Ro/SSA immunoglobindeposition in human skin (Lee, L. A., et al., J. Clin. Invest.83:1556-1562 (1989)) have been demonstrated. Specific concentration ofanti-Ro/SSA has been shown in the immunoglobulin of renal eluates fromkidneys affected by lupus nephritis (Maddison, P. J. and Reichlin, M.Arthritis Rheum. 22:858-863 (1979)). Anti-Ro/SSA has been found to bespecifically concentrated in a parotid gland of a patient with Sjogren'ssyndrome and primary biliary cirrhosis (Penner, E. and Reichlin, M.Arthritis Rheum. 25:1250-1253 (1982)). Observations that infants withtransplacentally acquired maternal IgG develop neonatal lupus dermatitisand/or complete congenital heart block (Harley, J. B. and Gaither, K.K.: Autoantibodies. In Rheumatic Disease Clinics of North America:Systemic Lupus Erythematosus 14:1, 43-56 (1988)) strongly suggests thatmaternal autoantibody (anti-Ro/SSA or anti-La/SSB) transported acrossthe placenta is a critical component required, but not sufficient, forthese clinical problems.

The Ro/SSA family of proteins has now been shown to have severalmolecular forms which are operationally defined by the molecular weightof the antigen identified. A major form has an apparent molecular weightof 60 kiloDaltons (kD). This protein is associated with one of four hYRNAs. Recently, two additional proteins bound by anti-Ro/SSA sera havebeen identified by M. D. Rader, et al., J. Clin. Invest. 83:1556-1562(1989), with molecular weights of 52 kD and 54 kD. A 48 kD protein,calmodulin, has been identified as being bound by anti-Ro/SSA sera(McCauliffe, et al., J. Clin. Invest. 85:1379-1391 (1990)). The La/SSBprotein, a 48 kD peptide, as described by J. C. Chambers and J. D.Keene, Proc. Natl. Acad. Sci. USA 82:2115-2119 (1985), is also a memberof this group of autoantibodies, and binds small RNAs with a polyuridineterminus, as reported by J. E. Stephano, Cell 36:145-154 (1984). La/SSBis bound by a third of the anti-Ro/SSA precipitin positive sera. TheLa/SSB protein has been purified from a variety of tissue sources andshown to be a 46 to 50 kD monomeric phosphoprotein, as reported byHabets, et al., EMBO J. 2:1625 (1983) and Venables, et al., Clin. Exp.Immunol. 54:731 (1983). It associates with RNA polymerase IIItranscripts, as reported by Lerner, et al., Proc. Natl. Acad. Sci. USA.76:5495 (1979) and Steitz, et al., Cold Spring Harbor Symposium Quant.Biol. 47:893 (1983), and may function as a termination factor for thisenzyme, as reported by Gottlieb, et al., EMBO J. 8:841 (1989). A nucleicacid dependent ATPase/dATPase enzymatic activity has also beenattributed to La/SSB by Bachmann, et al., Cell 60:85 (1990).

Anti-Sm antibodies are frequently associated with SLE. Theseautoantibodies precipitate snRNP containing the U1, U2, U4/U6 and U5RNA. These complexes form the spliceosome and splice heterogenousnuclear RNA, as reported by Sharp, Science 235:766 (1987) and Maniatisand Reed, Nature 325:673 (1987). Anti-Sm antibodies are directed againstone or a combination of six polypeptides: B (26 kDa), B′ (27 kDa), D (13kDa), E/F (11 kDa doublet) and G (less than 10 kDa).

Nearly all rheumatic disease patients who form an anti-Sm precipitin inouchterlony immunodiffusion have or eventually develop an anti-nRNPprecipitin, as reported by Fisher, et al., Arthritis Rheum. 28:1348(1985). Anti-Sm and anti-nRNP precipitins form a line of partialidentify in Ouchterlony immunodiffusion, as discussed by Mattioli andReichlin, J. Immunol. 110:1318 (1973). The basis for this partiallyshared antigenicity is explained by the composition of the U snRNPparticles. The antigen for the anti-nRNP precipitin are the 70 kD, A,and C peptides that are unique to the U1 snRNP, B/B′ and D peptides arealso found on the U1 snRNP. The B/B′ and D Ag, but not the 70 kDa, A orC, are found in the U2, U4/U6 and U5 snRNP. Hence, both anti-Sm andanti-nRNP bind anti-U1 snRNP activity, but only anti-Sm binds U2, U4/U6,and U5 snRNP.

U.S. Ser. No. 07/648,205 filed Jan. 31, 1991 by John B. Harley for“Assays and Treatments for Autoimmune Diseases”, and U.S. Ser. No.07/472,947 entitled “Assays and Treatments for Autoimmune Diseases”filed Jan. 31, 1990, described a specific method to identify theetiologic or antigenic agent responsible for the production ofautoantibodies characteristic of a particular disorder. The antigen isfirst isolated, using, for example, autoantibodies isolated from one ormore patients. The antigen is then divided into overlapping short aminoacid sequences, preferably twenty amino acids or less, most convenientlyoctapeptides. The sequences having the greatest reactivity with theautoantibodies are identified and then compared with all known aminoacids sequences using the available computer data bases. The proteinhaving the maximum number or proportion of sequences homologous to thesequences of greatest reactivity with the autoantibodies is among thelikeliest candidate of the known sequenced proteins for the etiologicalagent or immunogen. Once the etiological agent and antigenic sequencesare known, it is possible to design assays and reagents for thediagnosis and treatment of patients having either the etiological agentand/or autoantibodies.

The examples in the earlier applications used peptides derived from thesequence for the 60 kDa Ro/SSA protein and La/SSB, which were reactivewith antisera from SLE and SS patients.

It is therefore an object of the present invention to provide additionaldiagnostic reagents for identifying and classifying individualspreviously exposed to a particular immunogen or expressingautoantibodies reactive with Ro/SSA, La/SSB, nRNP, or Sm B/B′polypeptides, or the epitopes (or their immune equivalent) elicitingproduction of the autoantibodies.

It is a still further object of the present invention to provide methodsand compositions for identifying and treating autoimmune disorders, suchas Systemic Lupus Erythematosus and Sjogren's syndrome.

SUMMARY OF THE INVENTION

A number of octapeptides have been generated from the sequences encodingthe 60 kDa Ro/SSA peptide, the La/SSB autoantigen, the 70 kD nuclearribonucleoprotein (nRNP), and the Sm B/B′ polypeptide, which representlinear epitopes for autoantibodies present in the sera of SLE and SSpatients.

For example, the most important antigenic peptides derived from Sm B/B′are (29) GTFKAFDK (SEQ ID NO:1), (45) CDEFRKIKPKNAKQP (SEQ ID NO:2),(94) RVPLAGAA (SEQ ID NO:3), (101) AGGPGVGRAAGRGVPAG (SEQ ID NO:4),(125) AGLAGPVRGVGGPSQ (SEQ ID NO:5), (140) QVMTPQGRGTVA (SEQ ID NO:6),(165) PTQYPPGRGTPPPPV (SEQ ID NO:7), (174) TPPPPVGRATPPPGI (SEQ IDNO:8), (184) PPPGIMAP (SEQ ID NO:9), (189) MAPPPGMRPPM (SEQ ID NO:10),(202) PIGLPPARGTPIGMPP (SEQ ID NO:11), (212) PIGMPPP (SEQ ID NO:12),(221) RPPPPGIRGPP (SEQ ID NO:13), and (228) RGPPPPGMRPPR (SEQ ID NO:14).Additional reactive peptides can be derived from (30) TFKAFDKHM (SEQ IDNO:15), (83) EGPPPKDT (SEQ ID NO:16), (88) KDTGIARV (SEQ ID NO:17), AND(120) IPQAPAGLAG (SEQ ID NO:18). These were determined by bindingstudies. PPPGMRPP (SEQ ID NO:123) is especially antigenic and isrepeated three times in the sequence of B/B′. The antigenicity of otherpeptides was determined and include the shorter peptides PPPGMRP (SEQ IDNO:124) and PPPGMR (SEQ ID NO:125). Substitution studies were also done.All 19 of the other common naturally occurring amino acids aresubstituted for an amino acid in a particular position. For example, thearginine in position six of PPPGMRPP (SEQ ID NO:123) can be substitutedwith: F, G, H, I, K, S, T, V, W and Y.

These peptides are useful in solid phase assays for patientscharacterized by the presence of these autoantibodies, and can be usedto categorize patients as to the likelihood of developing certainconditions associated with SLE. The peptides are also potentially usefulin treatment of these patients using immobilized peptide to removeaujtoantibody, to block binding of the autoantibodies with patientmolecules reactive with the autoantibodies, or as a component of avaccine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphs the antigenic regions of Sm B/B′, with the octapeptidesbinding with an absorbance greater than 0.50, and their surroundingoctapeptides. The following octapeptides are studied: IGTFKAFD (SEQ IDNO:168), GTFKAFDK (SEQ ID NO: 1), TFKAFDKH (SEQ ID NO:169), DCDEFRKI(SEQ ID NO:170), CDEFRKIK (SEQ ID NO:171), DEFRKIKP (SEQ ID NO: 172),EFRKIKPK (SEQ ID NO:173), FRKIKPKN (SEQ ID NO:174), RKIKPKNA (SEQ IDNO:175), KIKPKNAK (SEQ ID NO:176), IKPKNAKQ (SEQ ID NO:177), KPKNAKQP(SEQ ID NO: 178), PKNAKQPE (SEQ ID NO:179), QQVMTPQG (SEQ ID NO: 182),QVMTPQGR (SEQ ID NO:183), VMTPQGRG (SEQ ID NO:184), MTPQGRGT (SEQ ID NO:185), TPQGRGTV (SEQ ID NO: 186), PQGRGTVA (SEQ ID NO: 187), QGRGTVAA(SEQ ID NO:188), APTQYPPG (SEQ ID NO:189), PTQYPPGR (SEQ ID NO:190),TQYPPGRG (SEQ ID NO:191), QYPPGRGT (SEQ ID NO:192), YPPGRGTP (SEQ IDNO:193), PPGRGTPP (SEQ ID NO: 194), PGRGTPPP (SEQ ID NO: 195), GRGTPPPP(SEQ ID NO: 196), RGTPPPPV (SEQ ID NO: 197), GTPPPPVG (SEQ ID NO:198),IMAPPPGM (SEQ ID NO: 200), MAPPPGMR (SEQ ID NO:201), APPPGMRP (SEQ IDNO:202), PPPGMRPP (SEQ ID NO: 123), PPGMRPPM (SEQ ID NO:203), IGMPPPGM(SEQ ID NO: 205), GMPPPGMR (SEQ ID NO:206), MPPPGMRP (SEQ ID NO: 208),PPPGMRPP (SEQ ID NO: 123), PPGMRPPP (SEQ ID NO:209), MRPPPPGI (SEQ IDNO: 210), RPPPPGIR (SEQ ID NO:211), PPPPGIRG (SEQ ID NO:213), PPPGIRGP(SEQ ID NO: 127), PPGIRGPP (SEQ ID NO: 214), RGPPPPGM (SEQ ID NO:215),GPPPPGMR (SEQ ID NO: 216), PPPPGMRP (SEQ ID NO: 217), PPPGMRPP (SEQ IDNO: 123), PPGMRPPR (SEQ ID NO:218).

FIG. 2 graphs the results of deletion studies on the Sm B/B′ epitopePPPGMRPP (SEQ ID NO: 123): FIG. 2a, shows the decrease in binding forremoval of amino acids from the epitope. The following sequences arestudied: PPPGMRPP (SEQ ID NO:123), PPPGMRP (SEQ ID NO:124), PPPGMR (SEQID NO:125), PPPGM (SEQ ID NO:129), PPPG (SEQ ID NO:130), PPGM (SEQ IDNO:131), PGMR (SEQ ID NO:132), GMRP (SEQ ID NO:133), PPPP (SEQ IDNO:134); FIG. 2b shows the effect of substitution of the sixth positionarginine.

DETAILED DESCRIPTION OF THE INVENTION

A number of peptides, preferably consisting of eight amino acids, aredisclosed that are bound by human autoantibodies characteristic of SLEand other autoimmune disorders. The peptides are made synthetically,based on the published amino acid sequences for known autoantigens,Ro/SSA, La/SSB, nRNP, and Sm B/B′. They have a variety of uses, forexample, as components in diagnostic assays, potentially astherapeutics, and in research on the possible causes of these autoimmunediseases.

Definition of Linear Epitopes and Methods of Synthesis

As used herein, a peptide is defined as consisting of less than onehundred amino acids and will generally be an octapeptide. Peptides of upto forty amino acids, more preferably of between four and twenty-fiveamino acids, can be synthesized using any one of the methods known tothose skilled in the art. A preferred method is described in the detailin the examples. The octapeptides described in the examples herein arederived from published sequences encoding the autoantigens. The numberin parenthesis is the position in the sequence for the first amino acidresidue of the first octapeptide that binds. The underlined part of thesequences are the octapeptides with the greatest binding.

Although described with reference to specific sequences, a number ofsubstitutions using natural or synthetic amino acids can be made in thepeptides to yield an peptide acting as a linear epitope that isfunctionally equivalent to the disclosed sequence, as demonstrated byexamples 3 and 4. Accordingly, the term linear epitope as defined by aspecific sequence is used herein to include peptides havingsubstitutions yielding a peptide bound in an equivalent manner or extentby an antibody.

For example, using monoclonal antibodies against peptide determinants ofSm B/B′, substitution studies demonstrated that A, G, and S cansubstitute for R in PPPGMRPP in the binding of one antibody, KSm3.Analogously, F, H, T, V and Y can substitute for I in PPPGIRGP in thebinding of KSm3.

While the monoclonal antibodies have great potential to be instructive,it is important to realize that the polyclonal autoimmune sera obtainedfrom patients may lead to much more complicated binding phenomena.

Screening of Peptides by Binding to Autoantibodies.

Solid phase binding of autoantibodies to peptides has proven useful forexamining sequential linear epitopes and defining important residues inepitope structure but is expected to be less useful in definingconformational epitopes or regions where two or more linear, but notsequential, epitopes are brought together by the tertiary structure. Inaddition, although many peptides will tend to assume conformations insolution that are not found in the native protein structure, trueepitopes may still be delineated by this method. Those peptides thattend to have a structure similar to that found in the native moleculewill be bound by a larger proportion of the autoantibodies that bind theanalogous sequence on the native protein and may even be bound withgreater affinity.

The examples below describe in detail how the peptides can besynthesized and screened for binding.

Use of Peptides in Treatment and Classification of Patients

Subsets of antigenic peptides have the potential to identify patients atrisk for particular clinical manifestations or patients in particularprognostic groups. The peptides disclosed herein can be used incombination in assays, such as the solid phase assay, to classifypatients.

Specifically, the peptides that are bound by autoantibodies in patientscharacterized by specific disorders, such as renal disease or centralnervous system involvement, are selected and combined in an assay, suchas an ELISA for a test to detect the collection autoantibodies that bindthis particular collection of peptides. Using a mixture of peptides mayincrease the efficiency and reliability of such assays, as compared withusing a single autoantigen, or a single peptide.

The peptides can be used in solution or immobilized to a solidsubstrate, such as a gel suitable for affinity chromatography, or amulti-well plate, using standard techniques such as the commerciallyavailable cyanogen bromide.

The peptides can be used therapeutically in combination with apharmaceutically acceptable carrier. The peptides can be administered ina dosage effective to block autoantibodies or as a vaccine to block theautoantibodies, by eliciting an immune response. The peptide acts as afunctional antagonist by binding to antibody that does not stimulate oractivate the immune cells and thereby block the immune response to theautoantigens.

Pharmaceutical carriers are known to those skilled in the art andinclude encapsulation of compounds for oral administration, for example,in an enteric coating or in combination with a binder such as stearateor lactose, or in solution. Acceptable solutions include sterile water,saline, and buffered solutions at physiological pH. Peptides used asvaccines can be administered orally, intramuscularly or subcutaneously.Other compounds will be administered according to standard proceduresused by those skilled in the art. As defined herein, a pharmaceuticalcarrier is usually inert by itself but may have biological activity. Forexample, a vaccine may consist of immunogenic peptides or proteins incombination with an adjuvant.

Alternatively, the peptides used for treatment might include peptideshomologous to an identified antigenic sequence. These peptides, eitherfree or bound to a carrier, could be delivered to a patient in order todecrease the amount of circulating antibody with a particularspecificity. In addition, knowledge of the cross-reacting epitopesbetween a foreign antigen and an autoantigen may allow for re-inductionof tolerance. It is well known in experimental models of the immuneresponse that the response can be suppressed and tolerance induced bytreatment with the antigen. Peptide therapy with the cross-reactingsequences may be a potential therapy in autoimmune diseases.

The amino acid sequences can also be used to make agents forneutralizing circulating antibodies or immobilized on substrates inextracorporeal devices for specific removal of autoantibodies, usingmethodology known to those skilled in the art.

The present invention will be further understood with reference to thefollowing non-limiting examples:

EXAMPLE 1 Identification of Linear Epitopes of the La/SSB Autoantigen

Patients and Methods

Pentide Synthesis

The La/SSB amino acid sequence as predicted from the nucleotide sequenceof cDNA clones was as reported by Chambers, et al., J. Biol. Chem.263:18043 (1988) and Sturgess, et al., J. Immunol. 140:3212 (1988), theteachings of which are incorporated herein. The presumably complete 408amino acid La/SSB peptide sequence was used to construct simultaneouslysequential octapeptides, each overlapping its neighbor by seven aminoacids, on polystyrene pins. The entire amino acid sequence of the La/SSBprotein was synthesized on five blocks of 96 pins in an 8×12 format.Onto each pin block, three identical positive control octapeptides weresynthesized with the sequence EYRKKMDI, which represents a major epitopefrom the carboxyl terminal sequence of the human 60 kD Ro/SSA protein.Incubating dilutions of anti-Ro/SSA reference serum on these controlpins during each assay made comparisons possible among plates andbetween assays.

Solid Phase Anti-peptide Assay

All steps were carried out by immersing the pin blocks into microtiterplate wells. Pins were incubated in blocking buffer (1% bovine serumalbumin (BSA) in phosphate buffered saline (PBS), pH 7.2) for 1 h atroom temperature and then in 1:100 dilutions of sera in diluent (1% BSAand 0.05% Tween in PBS) overnight at 40° C. in humidified containers.Pin blocks were washed four times with wash buffer (0.05% Tween in PBS)for 10 min with agitation and then immersed for 1 heat room temperaturein affinity purified goat anti-human -chain specific antibody conjugatedto alkaline phosphatase (Sigma Chemical Co., St. Louis, Mo.) diluted1:1000 in diluent. After washing as above, pins were incubated inpara-nitrophenyl phosphate solution at 37° C. for 2 h. Color developmentwas read at 410 nm on a Dynatech MR5000 ELISA plate reader.

Regeneration of Pins

After substrate development, blocks of pins were incubated in a 50-60°C. sonicating water bath containing freshly prepared 1% sodium dodecylsulfate and 0.1% 2-mercaptoethanol for 1 h. They were then rinsed twicein distilled water, pre-heated to 50-60° C., and finally immersed inboiling methanol for 2 min prior to air drying.

Expression of Results

Variation within and among assays was standardized by normalizing Ro/SSApeptide positive control pins present on each block, which had beenincubated with anti-Ro/SSA reference serum at a dilution of 3:1000, to aconstant value of 0.175 at A₄₁₀. All absorbance data was thus normalizedby multiplication with the conversion factor A_(obs)/0.175, whereA_(obs) is the observed A₄₁₀ given by the Ro/SSA control pin incubatedwith 3:1000 anti-Ro/SSA reference serum for any given assay. Absorbancefor each octapeptide was plotted using a spreadsheet program (AOK.abcVersion 2.4) on a VAX 8250/VMS computer.

Samples

Sera from five normal, healthy donors and ten patients with primary SSand/or SLE were screened by pin ELISA for antibodies binding to theLa/SSB octapeptides. Eight of these ten patients had both anti-Ro/SSAand anti-La/SSB precipitin forming autoantibodies, and seven of theseeight had borne children with congenital heart block (CCHB). Twopatients had antibodies to Ro/SSA alone. Anti-La/SSB antibodies wereaffinity purified from the sera of two patients on La/SSB crosslinkedimmunosorbents as described by Horsfall, et al., J. Immunol. Meth.104:43 (1987).

Assessment of Linear Sequence Epitopes

Background binding was defined by the total average reactivity (A₄₁₀) offive normal sera to the entire La/SSB sequence (O.D.=0.333±0.128standard deviation). Regions of reactivity greater than or equal to 3.5standard deviations above background binding (equivalent to 0.9998 ofthe normal distribution) and bound by at least three patient sera weretaken to represent possible La/SSB epitopes. Epitopes were numbered inorder from most to least reactive. Operationally, this was defined firstby numbers of patients binding greater than or equal to 3.5 standarddeviations above the normal mean as a measure of the degree ofconservation between sera. As a secondary criterion, the averagemagnitude of peak reactivity among patients in the region of theputative epitope was used to rank epitopes having equal numbers ofpatient sera binding. In some cases an epitope could be a singleoctapeptide and in others a broad region of reactivity across severaloctapeptides was observed. In some of these latter cases, more than oneputative epitope was identified.

Results

Binding of Anti-La/SSB Antibodies to La/SSB Octapeptides

All eight anti-La/SSB positive patient sera have strongly bound selectedLa/SSB Octapeptides, which span the entire sequence from theamino-terminal to the carboxyl-terminal regions. Normal sera also bind,but at a much reduced level. Sera lacking anti-La/SSB antibodies, thoughpossessing high titers of other autoantibodies, have also shown lowreactivity to the La/SSB sequence, consistent with a backgroundresponse. Goat anti-human gamma-chain specific antibody conjugate usedin these studies does not significantly bind to the octapeptides in theabsence of human serum.

Epitopes Defined by Anti-La/SSB Sera from Patients

Positive reactivity has been defined as that greater than or equal to3.5 standard deviations above the mean reactivity of five normal sera tooverlapping octapeptides from the entire La/SSB sequence. Those regionswhich have been recognized by three or more anti-La/SSB sera have beendefined as possible epitopes in this study, although regions reactivewith one or two autoimmune sera may also constitute epitopes.

No epitope has been bound by all eight sera tested; however, 13 of the18 epitopes defined in this way have been bound by at least four sera.In addition, peak reactivity within each epitope tends to vary among thepatient sera, reflecting individual responses. Thus, although threepatients have bound octapeptides of epitope 18, their greatest bindinghas not been found to occur with the same octapeptide. Control sera alsohave minimal, though positive, binding to the La/SSB sequence by thiscriterion. More importantly, however, two other autoimmune sera with nodetectable anti-La/SSB antibodies do not bind any octapeptide from theLa/SSB sequence by a magnitude of 3.5 standard deviations above the meanof the normal sera.

Epitopes have been subsequently numbered from greatest to least, takingfirst into account the number of sera reacting, and second the relativemagnitude of the responses, as shown in Table I. Some of these epitopescorrespond to areas of high antigenic index or hydrophilicity aspredicted by Kyte and Doolittle plots, J. Mol. Biol. 157:105 (1982).

TABLE 1 La/SSB autoepitopes Number Position Sequence  1 136-153QVLNIQMRRTLHKAFKGS (SEQ ID NO:20)  2  17-37 ICHQIEYYFGDFNLPRDKFLK  3 46-57 WVPLEIMIKFNR (SEQ ID NO:21)  4  86-97 KKTKIRRSPSKPL (SEQ IDNO:22)  5  56-67 NRLNRLTTDFNVIVE (SEQ ID NO:23)  6 257-269 GEIKWIDFVRGAK(SEQ ID NO:24)  7 325-344 SLNKWKSKGRRFKGKGKGNK (SEQ ID NO:25)  8 292-303GNLQLRNKEVTW (SEQ ID NO:26)  9 154-162 IFVVFDSIE (SEQ ID NO:27) 10176-190 KETDLLILFKDDYFA (SEQ ID NO:28) 11 104-120 YKNDVKNRSVYIKGFPT (SEQID NO:29) 12  63-71 TDFNVIVEA (SEQ ID NO:30) 13 270-280 EGIILFKEKAK (SEQID NO:31) 14 354-367 KVQFQGKKTKFASD (SEQ ID NO:32) 15 246-253 REDLHILF(SEQ ID NO:33) 16 232-239 CLLKFSGD (SEQ ID NO:34) 17 379-386 TGPVKRAR(SEQ ID NO:35) 18 200-209 KVEAKLRAKQ (SEQ ID NO:36) Position refers toamino acids in the La/SSB sequence as numbered from the N terminus.Epitopes are defined as having reactivity of at least 3.5 S.d. abovebackground in at least three anti-La/SSB patient sera. Epitopes arenumbered from greatest to least in order of the extend of binding.Octapeptides of each putative epitope with the greatest binding areunderlined. In situations in which two octapeptides within a particularepitope have very similar binding, both are underlined.

Binding of Affinity Purified Anti-La/SSB Antibodies

Anti-La/SSB antibodies from two patients have been affinity purified onLa/SSB cross-linked immunosorbents. The affinity enriched anti-La/SSBpreparation from patient E11 is specifically increased in anti-La/SSBbinding activity relative to the serum which it was prepared. Theaffinity enriched preparation binds 17 of the 18 previously identifiedepitopes, the exception being epitope 17 (octapeptide 379); however,this preparation does bind octapeptides adjacent to epitope 17,particularly octapeptides 380 and 382. Those putative epitopes in whichthe binding is most enriched include epitopes 2, 3, 6, 9, 10, 12, 13 and15. These same epitopes appear enriched whether peak or averagereactivities for each putative epitope are compared. Essentially thesame results have been obtained from an affinity enriched preparation ofthe anti-La/SSB from a second patient. This demonstration of enhancedbinding with increased anti-La/SSB specific activity is powerfulevidence that at least these peptide sequences represent linear epitopesof the anti-La/SSB autoimmune response.

Reproducibility of La/SSB Pin ELISA

The reproducibility of anti-Ro/SSA reference serum binding to the Ro/SSAoctapeptide (EYRKKMDI) positive control pins has been followedthroughout the study, giving an average standard deviation betweenassays of 14.0% and 16.3% for pins incubated in 1:100 and 3:100anti-Ro/SSA reference serum, respectively. Sera with and withoutanti-La/SSB antibodies have also given equally consistent results whenrepeated in the pin ELISA.

Shared Sequences with Cardiac Related Proteins

Consecutive amino acid sequence identity is shared between the heavychain of human cardiac β-myosin and three linear regions in the La/SSBsequence, two of which coincide with La/SSB epitopes. Within epitopes 13(La/SSB amino acids 277 through 280), a four amino acid sequence isshared with cardiac β-myosin (sequence residues 453 through 456), whilethere is a shared pentapeptide within epitope 18 (204 through 208) andcardiac β-myosin (619 through 623). Three of five homologous sequencesshared with the M6 protein of Streptococcus pyogenes, the bacteriumassociated with rheumatic heart disease, fall within the La/SSBepitopes. Specifically, two pentapeptide matches occur in La/SSBepitopes 5 (59 through 63) and 18 (203 through 207), while atetrapeptide match is within epitope 13 (276 through 279). Strikingly,epitopes 13 and 18 also share amino acid sequence with the B1 chain oflaminin, an adherent glycoprotein found in all basement membranes,including the sarcolemmal membrane of heart. The region within epitope13 contains two overlapping tetrapeptide matches with laminin B1 (1202through 1205 and 1367 through 1370), coinciding with La/SSB amino acidresidues 277 through 280 and 275 through 278, respectively; while La/SSBepitope 18 (202 through 207) shares a six consecutive amino acids withlaminin B1 (1467 through 1472). Antibodies binding to these epitopeswere found in each of the seven sera from patients who had a child withCCHB.

EXAMPLE 2 Identification of Linear Epitopes of the 60 kD Ro/SSA Protein

Peptides that represent linear epitopes for the 60 kD protein, includingmany originally presented in the earlier application, are shown in Table2. These data represent the average result from seven normal sera, fouranti-Ro/SSA precipitin positive sera, and the anti-Ro/SSA affinitypurified autoantibody from the same four anti-Ro/SSA precipitin positivepatient sera. The data has been multiplied by a constant in each case sothat the magnitude of the binding could be compared at a constant IgGconcentration, 100 micrograms IgG per milliliter in these results.

This study demonstrates that the anti-Ro/SSA peptide binding activity isenriched in parallel with the anti-Ro/SSA activity directed against thenative molecule. The specific binding activity against both theantigenic peptides and the Ro/SSA antigen increased by about three-foldby the affinity enrichment procedure, indicating that peptide binding ispart of the overall anti-Ro/SSA response.

The first and second columns of Table 2 identify the sequences boundabove a threshold of A₄₁₀ of 0.3. This threshold was chosen because noneof the peptides were bound by the normal sera by an average of greaterthan A₄₁₀=0.3. The first column in Table 2 is from the average of fouranti-Ro/SSA precipitin sera and the second is from the affinity enrichedanti-Ro/SSA. In the third column are the antigenic sequences from whichthe antigenic octapeptides are composed. The superscript asterisk “*”identifies the octapeptide number of the octapeptide with the greatestbinding of any contiguous collection all with A₄₁₀ of at least 0.3. Thispart of the sequence is also underlined. If two octapeptides have anA₄₁₀ within 1% of each other then two octapeptide are identified with anasterisk and the amino acids contributing to both octapeptides areunderlined.

TABLE 2 Average binding of four anti-Ro/SSA sera and affinity enrichedanti-Ro/SSA preparations to octapeptides constructed from the sequenceof the 60 Kd Ro/SSA peptide greater than A₄₁₀ of 0.3. AffinityAnti-Ro/SSA Purified Sera Anti-Ro/SSA (Octapeptide (Octapeptide Number)Number) Sequence 30* MNRLHRFL (SEQ ID NO:37) 37-38* LCFGSEGGT (SEQ IDNO:38) 45* 45*-48 SEGGTYYIKEQ(SEQ ID NO:39) 47-48* 76-78*-79EIKSFSQEGRT(SEQ ID NO:40) 81-82 81-82* SQEGRTTKQ(SEQ ID NO:41) 84*-85GRTTKQEPM(SEQ ID NO:42) 106-108* 105-108*-109 ISTKQAAFKAVS(SEQ ID NO:43)111*-112 AFKAVSEVC(SEQ ID NO:44) 126-130*-133 126-130*-133FTFIQFKKDLKESMK(SEQ ID NO:45) 139*-140 138-139*-140* SMKCGMWGRA (SEQ IDNO:46) 143-145*-146 142-145*-146 GMWGRALRKAIA(SEQ ID NO:47) 165-169*-170165-173*-180 ALAVTKYKQRNGWSHKDLLRLSH(SEQ ID NO:48) 172-173* 183-184*182-184*-185 LLRLSHLKPSS(SEQ ID NO:49) 210* HELYKEKA (SEQ ID NO:50) 212*212*-213 LYKEKALSV(SEQ ID NO:51) 222* 216-222* KALSVETEKLLKYL (SEQ IDNO:52) 224* KLLKYLEA (SEQ ID NO:53) 231-234* 229-234* LEAVEKVKRTKDE (SEQID NO:54) 257*-261 257*-263*-271 HLLTNHLKSKEVWKALLQEMPL(SEQ ID NO:55)263-264*-265*-266 280*-283 280*-283 ALLRNLGKMTA(SEQ ID NO:56) 285*LGKMTANS (SEQ ID NO:57) 308-313*-315*-316 308-313*-315*-317LCNEKLLKARIHPFHI(SEQ ID NO:58) 330-331*-339 33O-331*-340TYKTGHGLRGKLWRPDE(SEQ ID NO:59) 352* ALDAAFYK (SEQ ID NO:60) 355*-357355*-367 AAFYKTFKTVEPTGKRFLLA(SEQ ID NO:61) 362*-365*-366 379*-381ASMNQRVLGS(SEQ ID NO:62) 398* AMCMVVTR (SEQ ID NO:63) 414* AFSDEMVP (SEQID NO:64) 420* VPCPVTTD (SEQ ID NO:65) 433* VLMAMSQI (SEQ ID NO:66) 445*TDCSLPMI (SEQ ID NO:67) 449*-450 447-449*-454 CSLPMIWAQKTNTPA(SEQ IDNO:68) 453* 472*-474 TFAGGVHPAI(SEQ ID NO:69) 482-484*-489 481-484*-489IALREYRKKMDIPAKL(SEQ ID NO:70) 197-201*-203 197-198*-205IVTKYITKGWKEVHEL(SEQ ID NO:71)

EXAMPLE 3 Identification of Linear Epitopes of the 70 kD NuclearRibonucleoprotein

The sequence of the 70 kD nuclear ribonucleoprotein (nRNP) is reportedby R. A. Spritz, et al., in Nucleic Acids Res. 24: 10373-10391 (1987),the teachings of which are incorporated herein. The data analysis isdone the same as for the Ro/SSA and La/SSB antigens. Each sequenceidentified represents the binding of antibody to octapetides that exceedarbitrary criteria in the solid phase assay. The identified antigenicregions are more than two standard deviations above the mean of normalsera and are bound by more than half of the patients. For the binding tothe 70 kD peptide, the threshold in the assay is A₄₁₀ of 0.380. Thenumbers in parentheses are the sequence positions of the first aminoacid in the first octapeptide that exceeds the threshold. Eachidentified sequence is composed of one or more octapeptides. The numberof octapeptides in each sequence is the length of the sequence minuseight. The underlined part of the sequence is the octapeptide that isbound most by the patient serum. In some cases, another octapeptide isessentially equivalent but not underlined.

The antigenic sequences of the 70 kD nRNP are: (11) ALFAPRDP (SEQ IDNO:72), (65) ERMERKRREK (SEQ ID NO:73), (133) HMVYSKRSGKPRGY (SEQ IDNO:74), (161) YKHADGKKIDGRRVL (SEQ ID NO:75), (178) VERGRTVK (SEQ IDNO:76), (184) VKGWRPER (SEQ ID NO:77), (264) RRSRSRDK (SEQ ID NO:78),(274), RRRSRERS (SEQ ID NO:79), (277) SRERSKDK (SEQ ID NO:80), (282)KDKDRDRKRRSSRSR (SEQ ID NO:81), and (355) RRSHRSER (SEQ ID NO:82).

The A peptide of nRNP has the following antigenic octapeptides: 916)NLNEKIKKD (SEQ ID NO:83), (21) IKKDELKKSL (SEQ ID NO:84, (44*)LVSRSLKMRGQAF (SEQ ID NO:85), (73) QGFPFYDKPMPI (SEQ ID NO:86), (93)IIAKMKGTF (SEQ ID NO:87), (103*) ERDRKREKRKPKS (SEQ ID NO:88), (116)QETPATKKA (SEQ ID NO:89), (263) ALQGFKIT (SEQ ID NO:90), and (274)AMKISFAKK (SEQ ID NO:91). The threshold defined as two standarddeviations above the mean is a normalized A₄₁₀ of 0.400. The octapeptidesequences identified by a (*) are bound by a subset of the sera tested.The sequences upon which this result is based is found in Sillekens, etal., EMBO J. 6:3841-3848 (1987), the teachings of which are incorporatedherein.

The C peptide of nRNP has the following antigenic octapeptides: (19)SVRKTHCSGRKHKENVKD (SEQ ID NO:92), (35) KDYYQKWM (SEQ ID NO:93), (56)AFQQGKIPP (SEQ ID NO:94), (61) KIPPTPFS (SEQ ID NO:95), (78) PPPPSLPG(SEQ ID NO:96), (82) SLPGPPRP (SEQ ID NO:97), (85) GPPRPGMMPA (SEQ IDNO:98), (108) PPPPGMMP (SEQ ID NO:99), (117) GPAPGMRPP (SEQ ID NO:100),(136) PPMMRPPA (SEQ ID NO:101), and (152) PGMTRPDR (SEQ ID NO:102). Thethreshold for binding of these octapeptides was A₄₁₀ of 0.440. Thesequence upon which this result is based is in Sillekens, et al.,Nucleic Acids Res. 25:8307-8321 (1988), the teachings of which areincorporated herein.

EXAMPLE 3 Linear Epitope Mapping of an Sm B/B′ Polypeptide

Autoantibodies binding the Sm B/B′ peptides are commonly associated withSLE IgG antibodies binding overlapping octapeptides of Sm B/B′ have beenevaluated in 10 patients with anti-Sm and anti-nRNP precipitins, 5patients with other autoimmune serology, and 4 normal human sera.Neither normal controls nor patients without an anti-Sm precipitinsignificantly bind any of the Sm B/B′ octapeptides. All sera testedcontaining an anti-Sm precipitin strongly bind octapeptides from eightregions of the Sm B/B′ sequence. Three of these eight regions share thesame octapeptide sequences (PPPGMRPPR (SEQ ID NO:123)), that areconsistently the most immunoreactive octapeptides from Sm B/B′. Bindingof the similar PPPGIRGP (SEQ ID NO:127), as well as binding to deletionand substitution peptides, suggest that the motif PPPG (I,M) (R,K)appears to best define this binding. PAPGMRPP (SEQ ID NO:116) in thenRNP C peptide is as antigenic as PPPGMRPP and may provide a partialexplanation for the cross-reactivity shown between Sm and nRNPautoantibodies. However, the sequence PPPGMIPP (SEQ ID NO:117) from nRNPA is not antigenic. These data define the linear sequenceautoantigenicity of the Sm B/B′ protein. They also demonstrate that thepredominant autoimmune epitope is a proline-rich sequence from whichlimited variance is permitted before antigenicity is destroyed.

Two sequences of Sm B/B′ have been reported. Rokeach et al., J. Biol.Chem. 264:5024 (1989) have obtained a sequence from a lymphoblastoidcell (Raji) library that is identical to a partial clone from HeLacells, reported by Sharpe, et al., FEB Lett. 250:585 (1989) and to Sm Nfrom a human cerebellar library reported by Schmauss, et al., NucleicAcids Res. 17:1733 (1989). Sm B and Sm B′ have very similar amino acidsequences, van Dam, et al., EMBO J. 8:3853 (1989). Indeed, it appears,that Sm B and Sm B′ are alternate splicing products from a commonpre-mRNA.

In this study overlapping octapeptides of the encoding regions of bothSm B/B′ sequences were synthesized by solid-phase peptide synthesis.Antigenicity of each octapeptide was determined with a variety of serafrom patients with SLE and normal controls.

Materials and Methods

Sera

Human sera form patients who satisfied the classification criteria ofthe American Rheumatism Association for SLE or normal age-matched,sex-matched controls were used in this study. Fifteen sera from lupuspatients were tested. Ten of these sera tested contained antibodies thatformed strong precipitin lines with both Sm and nRNP, three formedprecipitin lines with only nRNP, one formed a precipitin line withRo/SSA and La/SSB, and one formed a precipitin line with only Ro/SSA.All of these serologic findings were confirmed by appropriate molecularweight bands for the reported antigen being bound in immunoblot by therespective sera.

Solid-phase Noncleavable Peptide Synthesis

The published sequence of Sm B/B′ was used to construct all the possibleoverlapping octapeptides. The amino acids used for peptide synthesis hadFmoc protected primary amino groups and t-butyl (or other appropriategroup) protected side chains. Overlapping octapeptides weresimultaneously synthesized at the rounded ends of radiation derivatizedpolyethylene pins that were arranged in the format of a 96 wellmicroliter plate (Cambridge Research Biochemicals. Cambridge, UK andCoselco Mimotopes Pty Ltd. Victoria, Australia) The active esters ofFmoc, t-butyl amino acid solutions (30 mM) were solubilized in DMF thathad 10 hydroxybenzotriazole added to a final concentration of 30 mM anddispensed into the wells of a microliter plate. Each amino acid wasadded as determined by the 240 amino acids of the Raji Sm B/B′ sequence.After 18 h of incubation, the pins were washed in DMF for 5 min. fourtimes at 2 min each in methanol, and once again in DMF for 5 min. TheFmoc protecting groups were then removed from the newly added amino acidby a 20% piperidine/DMF bath for 30 min. These steps were repeated untilall eight amino acids were added. After the final amino acid, the aminoterminal groups of each peptide was acetylated by incubating the pins ina 5:2:1 (v/v/v) mixture of DMF:acetic anhydride: triethylamine for 90min at room temperature. After this step the pins were again washed inDMF for 2 min, four times at 2 min each in methanol, and then air-driedfor 10 min. Finally, side chain amino protecting groups were removed by95:2, 5:2.5 (v/w/v) of trifluoracetic acid:phenol:ethanedithiol. Washsteps included 2 min in methylene chloride, two times at 5 min each in5% diisopropylethylene/methylene chloride, and a final methylenechloride wash for 5 min. After drying for 10 min., pins were placed indistilled water for 2 min., transferred to a methanol bath for 18 h. anddried under vacuum for 18 h. This procedure was repeated to synthesizeanother set of the carboxyl-terminal 36 octapeptides to allowsubstantiation of the previous data. In addition other octapeptides,including the amino acid changes seen in the vanDam/Ohosone Proc. Natl.Acad. Sci. USA 86:4249 (1989) sequences, were also synthesized. Selectedsubstitution and deletion sequences, along with similar sequences fromother proteins, were also constructed. Control pins composed of aminoacids in a random sequence were prepared that were not present in any ofthe Sm or nRNP antigen sequences. In addition, positive control pinswere synthesized from a known reactive sequence of the La/SSB peptide.

Solid-phase Cleavable Peptide Synthesis

Coselco Mimotopes Pty Ltd. has developed a method of producing cleavablepeptides. These peptides are synthesized on polyethylene pins thatcontain a cleavable linker assembly that contains an additionalproline-lysine-alanine sequence. After synthesizing the peptide asdescribed above, a final 15-min sonication in 0.1% HCl (in 1:1methanol/ddH₂O) is added. Pins are incubated in a solution of equalamounts of 0.1 M citrate and 0.1 M phosphate buffer at pH 3.0 for 3 hwith gentle agitation. This removes all residual contaminants. Peptidesare then cleaved from the pins by incubation in a 0.1 M phosphatesolution at ph 7.0 that causes cyclization and formation of adiketopiperazole. These peptides were then analyzed for amino acidcontent. Four octapeptides were constructed as described and the correctamino acids in the proper ratios were present in all peptides tested.

Solid Phase Antipeptide Assay

Wash steps and incubations were carried out in sealed plasticcontainers. Other assay steps were performed by lowering the pins intomicroliter plate wells. First, pins were blocked with 3% low-fat milk inPBS for 1 h at room temperature. Pins were then incubated in 1/100dilutions of sera in 3% milk/PBS with 0.05% Tween overnight at 4° C. inhumidified sealed containers. The pin blocks were then washed four timeswith PBS with 0.05% Tween for 10 min each with vigorous agitation. Next,each pin was incubated with anti-human gamma-chain specific IgG raisedin a goat, affinity purified and conjugated to alkaline phosphatase(Jackson Immunoresearch Laboratories, West Grove, Pa.) at a 1/10,000dilution. Paranitrophenyl phosphate disodium was used as a substrate foralkaline phosphatase and plates were read at 405 nm with a MicroelisaReader (Dynatech, Alexandria, Va). Results for each plate were thenstandardized by comparison with positive control pins. The same controlpins were used for all plates and were allowed to develop to a specificOD with a known concentration of a standard control sera.

After completion of an assay, pins were sonicated for 2 h in sonicationbuffer (40 g SDS, 4 ml β-mercaptoethanol. and 62.4 g sodium phosphate to4 liters) to remove antibodies, conjugate, and substrate. Aftersonication pins were washed twice in hot water and boiled in methanolfor 2 min. Pins were then allowed to air dry for a minimum of 10 min andwere stored with desiccant or used for another assay.

Epitope Mapping of Sm B/B′

Peptides were first screened for reactivity with anti-human IgGconjugate alone. No background was demonstrated with anti-human IgGconjugate. Four normal human sera also showed minimal backgroundreactivity with no specific antigenic regions demonstrated. SLE patientswith autoimmune serology other than anti-Sm, anti-nRNP also showed noconvincing, specific reactivity with any of the octapeptides. Otherrheumatic serology tested included sera which formed precipitins withRo/SSA as well as with both Ro/SSA and La/SSB Ag. Every patient whoprecipitated Sm and nRNP, however, showed considerable reactivity withvarious regions of the Sm B/B′ protein. Ten Sm, nRNP sera were testedand all had a similar pattern of binding. Considerable reactivity wasdemonstrated in the proline-rich, carboxyl-terminal region of theprotein. A repeated motif, PPPGMRPP (SEQ ID NO:123), is found in threeregions of the Sm B/B′ polypeptide and is similarly antigenic in each.In addition, a closely related fourth region, PPPGIRGP (SEQ ID NO:127),is bound by all the Sm, nRNP sera tested.

Several other antigenic regions were also detected in the first andmiddle portions of the polypeptide. These regions were not stronglyreactive in all sera tested; however, they may be important by definingthe differences in the very fine specificity between individuals with anautoimmune response to the B/B′ Ag.

To elucidate which amino acids are essential for reactivity the averagebinding surrounding each purported epitope is presented along with thesequence of each relevant octapeptide in FIG. 1. The octapeptidestarting with amino acid 29, GTFKAFDK (SEQ ID NO:1), requires all eightresidues for reactivity. The antigenicity of the reactive area in theregion of octapeptide 45, however, appears to be based on a requirementfor two lysines with an intercalated amino acid spacer. Binding is lostin octapeptides 44 and 53 when the two lysines with intercalated spaceris eliminated.

The sequence from octapeptides 140 to 145 all have moderately elevatedaverage binding. Each shares a PQGR (SEQ ID NO:128), sequence that wouldappear to be critical for binding. The reactive site surroundingoctapeptide 169, on the other hand, is not easily explained by aspecific sequence. The repeated PPPGMRPP (SEQ ID NO:123) and the similarPPPGIRGP (SEQ ID NO:127) found at octapeptides 191, 216, 223, and 231share the hexamer, PPPGXR (SEQ ID NO:119), where X indicates anundetermined amino acid, in all of the octapeptides with the greatestbinding. This repeated motif appears to be important in the binding ofanti-Sm to linear epitopes of Sm B/B′.

Deletion experiments with PPPGMRPP (SEQ ID NO:123). Deletion experimentsof the PPPGMRP (SEQ ID NO:124) sequence demonstrated that not all eightamino acids are required for antigenicity with the six patient seratested, as shown in FIG. 2a. Peptides were synthesized that deleted thecarboxyl-terminal amino acid leaving a heptamer of PPPGMR (SEQ IDNO:124), a hexamer of PPPGMR (SEQ ID NO:125), a pentamer of PPPGM (SEQID NO:129), and various tetrameres including PPPG (SEQ ID NO:130), PPGM(SEQ ID NO:131), PGMR (SEQ ID NO:132), GMRP (SEQ ID NO:133), and PPPP(SEQ ID NO:134). Binding appears to require at least the hexamer PPPGMR(SEQ ID NO:125) before the significant reactivity is lost. Greater than60% of the reactivity to the PPPGMRP (SEQ ID NO:123) motif is destroyedwhen the sixth position arginine is removed. Removal of the carboxylterminal prolines does not appear to significantly alter binding in thesix patients tested. In addition no solely poly-proline sequence tested(PPPPP (SEQ ID NO:120), PPPP, (SEQ ID NO:135), PPP, PP) has shownreactivity with these sera. Six of the 10 sera containing anti-Sm andanti-nRNP were tested with these deleted peptides and gave similarresults. A normal serum did not bind any of these peptides.

Substitution experiments of PPPGMRPP (SEQ ID NO:123) antigenic sequence.Substitution of the arginine (R) with the other 19 naturally occurringamino acids demonstrated varying levels of reactivity with the six seratested, as shown in FIG. 2b. Substitution of the arginine by anotherpositively charged amino acid, lysine (K), preserves more than 75% ofthe original reactivity. Another subset of the nine amino acids(containing F, G, H, I, S, T, V, W, and Y) retain approximately 50 to65% of original binding, whereas the other nine amino acids reducebinding to less than 25%.

Synthesis of Various Similar Epitopes

Short sequences of various proteins that displayed considerable homologywith the PPPGMRPP (SEQ ID NO:123) motif were also synthesized onpolyethylene pins. These sequences and their reactivity, as measured bysix different patient sera with anti-Sm and anti-nRNP precipitins fromthe first experiments. Octapeptides from nRNP A (23), nRNP C (24), andthe EBV nuclear Ag-1 (25) were prepared. The nRNP A and one nRNP Csequence showed relatively no reactivity; however, the second nRNP Csequence (PAPGMRPP) (SEQ ID NO:116) showed over 90% of the originalbinding. In addition, the EBV sequence (which has five of six amino acidhomology with the required antigenic portion of PPPGMRPP) (SEQ IDNO:123) is also significantly bound by Sm, nRNP precipitin positivepatients.

All antigenic sites determined in this study require a positivelycharged amino acid. The size of these sites varies from twononconsecutive basic amino acids to an entire octapeptide. The PPPGMRPP(SEQ ID NO:123) motif appears to be the major linear antigenic epitopein all Sm, nRNP sera tested; however, this sequence does not appear tobe bound by sera that contain an anti-Sm precipitin in the absence of ananti-nRNP precipitin. Sm precipitin alone patients bind two regions ofSm B/B′.

The carboxyl-terminal di-proline of the PPPGMRPP (SEQ ID NO:125) motifis not required for antigenicity. Other deletion studies have also shownthat the antigenicity of these autoantibodies are not specificallydirected against the poly-proline regions. Peptides containing from twoto six polyprolines have shown no reactivity with the sera used in thisstudy. In addition, naturally occurring octapeptides of amino acidsequences 175-186 and 85-92 contain three or four consecutive prolines:none of these regions is antigenic. Also the very similar PPPGMIPP (SEQID NO:117) octapeptides does not bind to the sera precipitating Sm andnRNP.

Substitution experiments have shown that changing one amino acid canreduce reactivity of a sequence by more than 90%. Substituting the other19 naturally occurring amino acids for the sixth amino acid, arginine(R), of the PPPGMRPP (SEQ ID NO:123) sequence has divided these aminoacids into three separate groups. Lysine (K), another basic amino acid,is the only substitution that preserves an average of more than 75% ofthe binding. With each of the sera tested, this amino acid substitutionis consistently the most reactive. However, reactivity is ablated toless than 25% with nine amino acids. This set includes the acidic aminoacids and their amines, the sulfur-containing amino acids, and thehydrophobic leucine, proline, and alanine. The other nine amino acidsretain part, 42 to 65%, of the original binding. Phenylalanine wasconsistently the most reactive of this group. Nevertheless, the abilityof lysine to substitute for arginine leads to the hypothesis that apositively charged amino acid at this position is preferred for theantigenicity of this sequence.

EXAMPLE 4 Binding of Monoclonal Antibodies Against Peptide Determinantsof Sm B/B′

Autoantibodies binding the Sm B and B′ peptides (B/B′) are commonlyassociated with systemic lupus erythematosus in man and in MRL 1pr/1prmice. KSm 3 and KSm 5 were derived from an unmanipulated MRL 1pr/1prmouse using hybridoma monoclonal antibody technology. Supernatantscontaining KSm 3 and KSm 5 monoclonal antibodies were collected fromcloned murine hybridoma cell lines in RPMI 1640 with 10% fetal bovineserum, glutamine, penicillin and streptomycin. These monoclonalautoantibodies are both of the IgG2a subclass. The linear antigenicregions of these two anti-Sm B/B′ murine monoclonal autoantibodies havebeen mapped using overlapping octapeptides. Unique epitopes areidentified by each monoclonal. Monoclonal antibody KSm 5 recognizes thepeptide, PPPGMRPP (SEQ ID NO:123), which is repeated three times in theSm B polypeptide. KSm 3 binds best to two very similar, almostneighboring octapeptides, PPPGIRGP (SEQ ID NO:127) and PGIRGPPP (SEQ IDNO:121). The two monoclonals do not crossreact. Both of these regions ofSm B/B′ are major areas of antigenicity for human anti-Smautoantibodies. Amino acid deletion and substitution in antigenicoctapeptides show that binding to the KSm 5 epitope is lost with onlyslight modification. When the arginine in the sixth position PPPGMRPP(SEQ ID NO:123) is substituted KSm 5 binding is found in an unexpectedsubset of octapeptides. Molecular dynamic modelling suggests thatbinding may be associated with a shared peptide backbone structurerather than charge or hydrophobicity of the substituted amino acid. Incontrast, binding of KSm 3 to PPPGIRPP (SEQ ID NO:122) is abolished whenthe sixth position arginine is substituted by any other amino acid.These two murine autoantibodies bind distinct linear epitopes of Sm B/B′which are also bound by human anti-Sm B/B′ autoantibodies. The boundepitopes are proline rich and contain an arginine in the fourth or sixthposition. Thus, substitution at arginine and modelling experimentssuggest very different mechanisms of binding for KSm 3 and KSm 5. Aparticular peptide backbone conformation, conferred by some amino acidsidechains at Position 6 of the octapeptide PPPGMRPT (SEQ ID NO:123),may be involved in KSm 5 binding while KSm 3 binding requires thespecificity of the arginine side chain. Naturally arising autoantibodiesmay bind quite different features of similar peptide structures.

Substitution,of either the fifth or sixth position amino acids ofPPPGIRGP (SEQ ID NO:127) with all of the other nineteen naturallyoccurring amino acids shows unique patterns of reactivity. Substitutionof the sixth amino acid arginine (R) shows that no other amino acidallows any degree of binding. When the fifth position isoleucine (I) issubstituted, six of the twenty amino acids, phenylalanine (F), histidine(E) threonine (T), valine (V) and tyrosine (Y), allow over 50% of thebinding shown with the original octapeptide. Of these, threonine hasmore reactivity than the original octapeptide.

To determine structural motif common to peptides of either antigenicgroup, molecular dynamic simulations were performed for selectedpeptides which are antigenic to KSm 5 or KSm 3. A total of 2500structures representing a nanosecond trajectory in time were accumulatedfor each peptide, and analyzed by monitoring backbone dihedral angles.At least one prevalent conformer could be chosen for all peptides asobserved by a stable set of backbone dihedral angles. The root meansquare difference between the KSm 3 positive peptides PPPGIRGP (SEQ IDNO:127) and PGIRGPPP (SEQ ID NO:121) of 4.87 A for the backbone atoms ofeight residues indicates that there is no common backbone between thesetwo peptides.

In contrast, the binding of KSm 5 to peptides substituted for arginine(R) in the sixth position in PPPGMRPP (SEQ ID NO:123) suggest quitedifferent binding requirements. Amino acids with side chains,—(CH₃)₃—NH—C—NHNH₂, —CH₃, —OH, and —H, all were roughly-equivalent intheir ability to be bound by KSm 5. No feature of charge orhydrophobicity is shared by these amino acids. Also, lysine andhistidine, the amino acids usually considered most similar to arginine,could not substitute and preserve binding. The possibility of asignificant backbone conformation common to the native peptide PPPGMRPP(SEQ ID NO:123) off set by one or more amino acids in either directionwas ruled out using OVRLAP18. The best match was found for the first fewresidues of the backbone with no offset. Accordingly, the conformationmay play a role in binding.

Modifications and variations of the method and reagents of the presentinvention will be obvious to those skilled in the art from the foregoingdetailed description. Such modifications and variations are intended tocome within the scope of the appended claims.

SEQUENCE LISTING (1) GENERAL INFORMATION: (iii) NUMBER OF SEQUENCES: 218(2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv)ANTI-SENSE: NO (v) FRAGMENT TYPE: N-terminal (vi) ORIGINAL SOURCE: (A)ORGANISM: Homo sapiens (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (x) PUBLICATION INFORMATION: (A) AUTHORS: Harley, John B.(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Gly Thr Phe Lys Ala Phe Asp Lys1 5 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:Cys Asp Glu Phe Arg Lys Ile Lys Pro Lys Asn Ala Lys Gln Pro 1 5 10 15(2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:Arg Val Pro Leu Ala Gly Ala Ala 1 5 (2) INFORMATION FOR SEQ ID NO:4: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 4..11(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Ala Gly Gly Pro Gly Val Gly ArgAla Ala Gly Arg Gly Val Pro 1 5 10 15 Ala Gly (2) INFORMATION FOR SEQ IDNO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE:amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULETYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION:7..14 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Ala Gly Leu Ala Gly ProVal Arg Gly Val Gly Gly Pro Ser Gln 1 5 10 15 (2) INFORMATION FOR SEQ IDNO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE:amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULETYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION:3..10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Gln Val Met Thr Pro GlnGly Arg Gly Thr Val Ala 1 5 10 (2) INFORMATION FOR SEQ ID NO:7: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 8..15(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: Pro Thr Gln Tyr Pro Pro Gly ArgGly Thr Pro Pro Pro Pro Val 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:8:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:8: Thr Pro Pro Pro Pro Val Gly Arg AlaThr Pro Pro Pro Gly Ile 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:9: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:9: Pro Pro Pro Gly Ile Met Ala Pro 1 5(2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:10: Met Ala Pro Pro Pro Gly Met Arg Pro Pro Met 1 5 10 (2)INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:16 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 5..12 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:11: Pro Ile Gly Leu Pro Pro Ala Arg Gly Thr Pro Ile Gly Met Pro 1 510 15 Pro (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:12: Pro Ile Gly Met Pro Pro Pro Gly 1 5(2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:Arg Pro Pro Pro Pro Gly Ile Arg Gly Pro Pro 1 5 10 (2) INFORMATION FORSEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 3..10 (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION:6 (D) OTHER INFORMATION: /note= “The arginine at position 8 can besubstituted with F, G, H, I, K, S, T, V, and Y.” (xi) SEQUENCEDESCRIPTION: SEQ ID NO:14: Arg Gly Pro Pro Pro Pro Gly Met Arg Pro ProArg 1 5 10 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:15: Thr Phe Lys Ala Phe Asp Lys His Met1 5 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:Glu Gly Pro Pro Pro Lys Asp Thr 1 5 (2) INFORMATION FOR SEQ ID NO:17:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:17: Lys Asp Thr Gly Ile Ala Arg Val 1 5(2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:18: Ile Pro Gln Ala Pro Ala Gly Leu Ala Gly 1 5 10 (2) INFORMATIONFOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 4..16 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Gln Val Leu AsnIle Gln Met Arg Arg Thr Leu His Lys Ala Phe 1 5 10 15 Lys Gly Ser (2)INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 8..15 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:20: Ile Cys His Gln Ile Glu Tyr Tyr Phe Gly Asp Phe Asn Leu Pro 1 510 15 Arg Asp Lys Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:21: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:21: Trp Val Pro Leu Glu Ile Met Ile LysPhe Asn Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 3..10 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:22: Lys Thr Lys Ile Arg Arg Ser Pro SerLys Pro Leu 1 5 10 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:23: Asn Arg Leu Asn Arg Leu Thr Thr AspPhe Asn Val Ile Val Glu 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:24: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 4..13(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Gly Glu Ile Lys Trp Ile Asp PheVal Arg Gly Ala Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:25: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 6..13(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: Ser Leu Asn Lys Trp Lys Ser LysGly Arg Arg Phe Lys Gly Lys 1 5 10 15 Gly Lys Gly Asn Lys 20 (2)INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 5..12 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:26: Gly Asn Leu Gln Leu Arg Asn Lys Glu Val Thr Trp 1 5 10 (2)INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 2..9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:Ile Phe Val Val Phe Asp Ser Ile Glu 1 5 (2) INFORMATION FOR SEQ IDNO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 7..14 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: Lys Glu Thr AspLeu Leu Ile Leu Phe Lys Asp Asp Tyr Phe Ala 1 5 10 15 (2) INFORMATIONFOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 9..16 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Tyr Lys Asn AspVal Lys Asn Arg Ser Val Tyr Ile Lys Gly Phe 1 5 10 15 Pro Thr (2)INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:Thr Asp Phe Asn Val Ile Val Glu Ala 1 5 (2) INFORMATION FOR SEQ IDNO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: Glu Gly Ile IleLeu Phe Lys Glu Lys Ala Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:32: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 7..14(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: Lys Val Gln Phe Gln Gly Lys LysThr Lys Phe Ala Ser Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO:33: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:33: Arg Glu Asp Leu His Ile Leu Phe 1 5(2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:Cys Leu Leu Lys Phe Ser Gly Asp 1 5 (2) INFORMATION FOR SEQ ID NO:35:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:35: Thr Gly Pro Val Lys Arg Ala Arg 1 5(2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:36: Lys Val Glu Ala Lys Leu Arg Ala Lys Gln 1 5 10 (2) INFORMATIONFOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Met Asn Arg LeuHis Arg Phe Leu 1 5 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:38: Leu Cys Phe Gly Ser Glu Gly Gly Thr1 5 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:Ser Glu Gly Gly Thr Tyr Tyr Ile Lys Glu Gln 1 5 10 (2) INFORMATION FORSEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: Glu Ile Lys SerPhe Ser Gln Glu Gly Arg Thr 1 5 10 (2) INFORMATION FOR SEQ ID NO:41: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:41: Ser Gln Glu Gly Arg Thr Thr Lys Gln1 5 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:Gly Arg Thr Thr Lys Gln Glu Pro Met 1 5 (2) INFORMATION FOR SEQ IDNO:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 4..11 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: Ile Ser Thr LysGln Ala Ala Phe Lys Ala Val Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:44:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:44: Ala Phe Lys Ala Val Ser Glu Val Cys1 5 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 5..12 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:45: Phe Thr Phe Ile Gln Phe Lys Lys Asp Leu Lys Glu Ser Met Lys 1 510 15 (2) INFORMATION FOR SEQ ID NO:46: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A)NAME/KEY: Binding-site (B) LOCATION: 2..10 (xi) SEQUENCE DESCRIPTION:SEQ ID NO:46: Ser Met Lys Cys Gly Met Trp Gly Arg Ala 1 5 10 (2)INFORMATION FOR SEQ ID NO:47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:47: Gly Met Trp Gly Arg Ala Leu Arg Lys Ala Ile Ala 1 5 10 (2)INFORMATION FOR SEQ ID NO:48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:23 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 9..16 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:48: Ala Leu Ala Val Thr Lys Tyr Lys Gln Arg Asn Gly Trp Ser His 1 510 15 Lys Asp Leu Leu Arg Leu Ser His 20 (2) INFORMATION FOR SEQ IDNO:49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: Leu Leu Arg LeuSer His Leu Lys Pro Ser Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:50: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:50: His Glu Leu Tyr Lys Glu Lys Ala 1 5(2) INFORMATION FOR SEQ ID NO:51: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:Leu Tyr Lys Glu Lys Ala Leu Ser Val 1 5 (2) INFORMATION FOR SEQ IDNO:52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 7..14 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: Lys Ala Leu SerVal Glu Thr Glu Lys Leu Leu Lys Tyr Leu 1 5 10 (2) INFORMATION FOR SEQID NO:53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: Lys Leu Leu LysTyr Leu Glu Ala 1 5 (2) INFORMATION FOR SEQ ID NO:54: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 6..13 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:54: Leu Glu Ala Val Glu Lys Val Lys ArgThr Lys Asp Glu 1 5 10 (2) INFORMATION FOR SEQ ID NO:55: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..14 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:55: His Leu Leu Thr Asn His Leu Lys SerLys Glu Val Trp Lys Ala 1 5 10 15 Leu Leu Gln Glu Met Pro Leu 20 (2)INFORMATION FOR SEQ ID NO:56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:Ala Leu Leu Arg Asn Leu Gly Lys Met Thr Ala 1 5 10 (2) INFORMATION FORSEQ ID NO:57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: Leu Gly Lys MetThr Ala Asn Ser 1 5 (2) INFORMATION FOR SEQ ID NO:58: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 6..15 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:58: Leu Cys Asn Glu Lys Leu Leu Lys LysAla Arg Ile His Pro Phe 1 5 10 15 His Ile (2) INFORMATION FOR SEQ IDNO:59: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 2..9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: Thr Tyr Lys ThrGly His Gly Leu Arg Gly Lys Leu Lys Trp Arg 1 5 10 15 Pro Asp Glu (2)INFORMATION FOR SEQ ID NO:60: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:Ala Leu Asp Ala Ala Phe Tyr Lys 1 5 (2) INFORMATION FOR SEQ ID NO:61:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:61: Ala Ala Phe Tyr Lys Thr Phe Lys ThrVal Glu Pro Thr Gly Lys 1 5 10 15 Arg Phe Leu Leu Ala 20 (2) INFORMATIONFOR SEQ ID NO:62: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: Ala Ser Met AsnGln Arg Val Leu Gly Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO:63: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:63: Ala Met Cys Met Val Val Thr Arg 1 5(2) INFORMATION FOR SEQ ID NO:64: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:Ala Phe Ser Asp Glu Met Val Pro 1 5 (2) INFORMATION FOR SEQ ID NO:65:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:65: Val Pro Cys Pro Val Thr Thr Asp 1 5(2) INFORMATION FOR SEQ ID NO:66: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:Val Leu Met Ala Met Ser Gln Ile 1 5 (2) INFORMATION FOR SEQ ID NO:67:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:67: Thr Asp Cys Ser Leu Pro Met Ile 1 5(2) INFORMATION FOR SEQ ID NO:68: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:68: Cys Ser Leu Pro Met Ile Trp Ala Gln Lys Thr Asn Thr Pro Ala 1 510 15 (2) INFORMATION FOR SEQ ID NO:69: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A)NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQID NO:69: Thr Phe Ala Gly Gly Val His Pro Ala Ile 1 5 10 (2) INFORMATIONFOR SEQ ID NO:70: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 4..11 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: Ile Ala Leu ArgGlu Tyr Arg Lys Lys Met Asp Ile Pro Ala Lys 1 5 10 15 Leu (2)INFORMATION FOR SEQ ID NO:71: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:16 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:71: Ile Val Thr Lys Tyr Ile Thr Lys Gly Trp Lys Glu Val HisGlu Leu 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:72: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:72: Ala Leu Phe Ala Pro Arg Asp Pro 1 5(2) INFORMATION FOR SEQ ID NO:73: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:Glu Arg Met Glu Arg Lys Arg Arg Glu Lys 1 5 10 (2) INFORMATION FOR SEQID NO:74: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 2..9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74: His Met Val TyrSer Lys Arg Ser Gly Lys Pro Arg Gly Tyr 1 5 10 (2) INFORMATION FOR SEQID NO:75: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 6..13 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75: Tyr Lys His AlaAsp Gly Lys Lys Ile Asp Gly Arg Arg Val Leu 1 5 10 15 (2) INFORMATIONFOR SEQ ID NO:76: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 aminoacids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: Val Glu Arg GlyArg Thr Val Lys 1 5 (2) INFORMATION FOR SEQ ID NO:77: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:77: Val Lys Gly Trp Arg Pro Arg Arg 1 5(2) INFORMATION FOR SEQ ID NO:78: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:Arg Arg Ser Arg Ser Arg Asp Lys 1 5 (2) INFORMATION FOR SEQ ID NO:79:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:79: Arg Arg Arg Ser Arg Glu Arg Ser 1 5(2) INFORMATION FOR SEQ ID NO:80: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:Ser Arg Glu Arg Ser Lys Asp Lys 1 5 (2) INFORMATION FOR SEQ ID NO:81:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 8..15(xi) SEQUENCE DESCRIPTION: SEQ ID NO:81: Lys Asp Lys Asp Arg Asp Arg LysArg Arg Ser Ser Arg Ser Arg 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:82:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:82: Arg Arg Ser His Arg Ser Glu Arg 1 5(2) INFORMATION FOR SEQ ID NO:83: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 2..9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:Asn Leu Asn Glu Lys Ile Lys Lys Asp 1 5 (2) INFORMATION FOR SEQ IDNO:84: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 2..9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84: Ile Lys Lys AspGlu Leu Lys Lys Ser Leu 1 5 10 (2) INFORMATION FOR SEQ ID NO:85: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 3..10(xi) SEQUENCE DESCRIPTION: SEQ ID NO:85: Leu Val Ser Arg Ser Leu Lys MetArg Gly Gln Ala Phe 1 5 10 (2) INFORMATION FOR SEQ ID NO:86: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 4..11(xi) SEQUENCE DESCRIPTION: SEQ ID NO:86: Gln Gly Phe Pro Phe Tyr Asp LysPro Met Arg Ile 1 5 10 (2) INFORMATION FOR SEQ ID NO:87: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:87: Ile Ile Ala Lys Met Lys Gly Thr Phe1 5 (2) INFORMATION FOR SEQ ID NO:88: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 3..10 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:88: Glu Arg Asp Arg Lys Arg Glu Lys Arg Lys Pro Lys Ser 1 5 10 (2)INFORMATION FOR SEQ ID NO:89: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:Gln Glu Thr Pro Ala Thr Lys Lys Ala 1 5 (2) INFORMATION FOR SEQ IDNO:90: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE:amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULETYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90: Ala Leu Gln GlyPhe Lys Ile Thr 1 5 (2) INFORMATION FOR SEQ ID NO:91: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:91: Ala Met Lys Ile Ser Phe Ala Lys Lys1 5 (2) INFORMATION FOR SEQ ID NO:92: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 10..17 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:92: Ser Val Arg Lys Thr His Cys Ser Gly Arg Lys His Lys Glu Asn 1 510 15 Val Lys Asp (2) INFORMATION FOR SEQ ID NO:93: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:93: Lys Asp Tyr Tyr Gln Lys Trp Met1 5 (2) INFORMATION FOR SEQ ID NO:94: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:Ala Phe Gln Gln Gly Lys Ile Pro Pro 1 5 (2) INFORMATION FOR SEQ IDNO:95: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE:amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULETYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION:1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95: Lys Ile Pro Pro Thr ProPhe Ser 1 5 (2) INFORMATION FOR SEQ ID NO:96: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:96: Pro Pro Pro Pro Ser Leu Pro Gly 1 5(2) INFORMATION FOR SEQ ID NO:97: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:Ser Leu Pro Gly Pro Pro Arg Pro 1 5 (2) INFORMATION FOR SEQ ID NO:98:(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 2..9 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:98: Gly Pro Pro Arg Pro Gly Met Met ProAla 1 5 10 (2) INFORMATION FOR SEQ ID NO:99: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:99: Pro Pro Pro Pro Gly Met Met Pro 1 5(2) INFORMATION FOR SEQ ID NO:100: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Binding-site (B) LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ IDNO:100: Gly Pro Ala Pro Gly Met Arg Pro Pro 1 5 (2) INFORMATION FOR SEQID NO:101: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Binding-site (B)LOCATION: 1..8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101: Pro Pro Met MetArg Pro Pro Ala 1 5 (2) INFORMATION FOR SEQ ID NO:102: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(ix) FEATURE: (A) NAME/KEY: Binding-site (B) LOCATION: 1..8 (xi)SEQUENCE DESCRIPTION: SEQ ID NO:102: Pro Gly Met Thr Arg Pro Asp Arg 1 5(2) INFORMATION FOR SEQ ID NO:103: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:103: Lys Trp Ile Asp Phe Val Arg Gly Ala Lys 1 5 10 (2)INFORMATION FOR SEQ ID NO:104: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:104: Ile Asp Phe Val Arg Gly Ala Lys 1 5 (2) INFORMATION FORSEQ ID NO:105: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105: Lys SerLys Gly Arg Arg Phe Lys 1 5 (2) INFORMATION FOR SEQ ID NO:106: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106: Leu Arg Asn Lys GluVal Thr Trp 1 5 (2) INFORMATION FOR SEQ ID NO:107: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:107: Phe Val Val Phe Asp Ser IleGlu 1 5 (2) INFORMATION FOR SEQ ID NO:108: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:108: Ile Leu Phe Lys Asp Asp Tyr Phe 1 5 (2)INFORMATION FOR SEQ ID NO:109: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:109: Ser Val Tyr Ile Lys Gly Phe Pro 1 5 (2) INFORMATION FORSEQ ID NO:110: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110: Thr AspPhe Asn Val Ile Val Glu 1 5 (2) INFORMATION FOR SEQ ID NO:111: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111: Asp Phe Asn Val IleVal Glu Ala 1 5 (2) INFORMATION FOR SEQ ID NO:112: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:112: Glu Gly Ile Ile Leu Phe LysGlu 1 5 (2) INFORMATION FOR SEQ ID NO:113: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:113: Lys Lys Thr Lys Phe Ala Ser Asp 1 5 (2)INFORMATION FOR SEQ ID NO:114: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:114: Glu Ala Lys Leu Arg Ala Lys Gln 1 5 (2) INFORMATION FORSEQ ID NO:115: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115: Cys PheGly Ser Glu Gly Gly Thr 1 5 (2) INFORMATION FOR SEQ ID NO:116: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116: Pro Ala Pro Gly MetArg Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO:117: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:117: Pro Pro Pro Gly Met Ile ProPro 1 5 (2) INFORMATION FOR SEQ ID NO:118: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:118: Asn Arg Leu Asn Arg Leu Thr Thr 1 5 (2)INFORMATION FOR SEQ ID NO:119: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:6 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY:Modified-site (B) LOCATION: 5 (D) OTHER INFORMATION: /note= “Xaa is anundetermined amino acid” (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119: ProPro Pro Gly Xaa Arg 1 5 (2) INFORMATION FOR SEQ ID NO:120: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:120: Pro Pro Pro Pro Pro 1 5 (2)INFORMATION FOR SEQ ID NO:121: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:121: Pro Gly Ile Arg Gly Pro Pro Pro 1 5 (2) INFORMATION FORSEQ ID NO:122: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122: Pro ProPro Gly Ile Arg Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO:123: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123: Pro Pro Pro Gly MetArg Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO:124: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:124: Pro Pro Pro Gly Met Arg Pro 15 (2) INFORMATION FOR SEQ ID NO:125: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 6 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:125: Pro Pro Pro Gly Met Arg 1 5 (2) INFORMATION FOR SEQ IDNO:126: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (ix) FEATURE: (D) OTHER INFORMATION: **former#219** (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126: Trp Ala Gln Lys Thr AsnThr Pro 1 5 (2) INFORMATION FOR SEQ ID NO:127: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:127: Pro Pro Pro Gly Ile Arg GlyPro 1 5 (2) INFORMATION FOR SEQ ID NO:128: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:128: Pro Gln Gly Arg 1 (2) INFORMATION FOR SEQ IDNO:129: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129: Pro ProPro Gly Met 1 5 (2) INFORMATION FOR SEQ ID NO:130: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:130: Pro Pro Pro Gly 1 (2)INFORMATION FOR SEQ ID NO:131: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:131: Pro Pro Gly Met 1 (2) INFORMATION FOR SEQ ID NO:132: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132: Pro Gly Met Arg 1 (2)INFORMATION FOR SEQ ID NO:133: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:133: Gly Met Arg Pro 1 (2) INFORMATION FOR SEQ ID NO:134: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134: Pro Pro Pro Pro 1 (2)INFORMATION FOR SEQ ID NO:135: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:4 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:135: Pro Pro Pro Pro 1 (2) INFORMATION FOR SEQ ID NO:136: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: aminoacid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136: Asn Ile Gln Met ArgArg Thr Leu His Lys Ala Phe Lys 1 5 10 (2) INFORMATION FOR SEQ IDNO:137: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137: Arg ThrLeu His Lys Ala Phe Lys 1 5 (2) INFORMATION FOR SEQ ID NO:138: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138: Tyr Phe Gly Asp PheAsn Leu Pro 1 5 (2) INFORMATION FOR SEQ ID NO:139: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:139: Val Pro Leu Glu Ile Met IleLys 1 5 (2) INFORMATION FOR SEQ ID NO:140: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:140: Lys Ile Arg Arg Ser Pro Ser Lys 1 5 (2)INFORMATION FOR SEQ ID NO:141: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:141: Glu Gly Gly Thr Tyr Tyr Ile Lys Glu Gln 1 5 10 (2)INFORMATION FOR SEQ ID NO:142: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:142: Gly Thr Tyr Tyr Ile Lys Glu Gln 1 5 (2) INFORMATION FORSEQ ID NO:143: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143: Gly ThrTyr Tyr Ile 1 5 (2) INFORMATION FOR SEQ ID NO:144: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:144: Lys Ser Phe Ser Gln Glu GlyArg 1 5 (2) INFORMATION FOR SEQ ID NO:145: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:145: Ser Thr Lys Gln Ala Ala Phe Lys Ala Val 1 510 (2) INFORMATION FOR SEQ ID NO:146: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:146: Lys Gln Ala Ala Phe Lys Ala Val 1 5 (2) INFORMATION FORSEQ ID NO:147: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147: Gln PheLys Lys Asp Leu Lys Glu 1 5 (2) INFORMATION FOR SEQ ID NO:148: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148: Met Lys Cys Gly MetTrp Gly Arg Ala 1 5 (2) INFORMATION FOR SEQ ID NO:149: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:149: Gly Arg Ala Leu Arg Lys AlaIle 1 5 (2) INFORMATION FOR SEQ ID NO:150: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:150: Thr Lys Tyr Lys Gln Arg Asn Gly 1 5 (2)INFORMATION FOR SEQ ID NO:151: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:151: Gln Arg Asn Gly Trp Ser His Lys 1 5 (2) INFORMATION FORSEQ ID NO:152: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152: Arg LeuSer His Leu Lys Pro Ser 1 5 (2) INFORMATION FOR SEQ ID NO:153: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153: Thr Lys Tyr Ile ThrLys Gly Trp 1 5 (2) INFORMATION FOR SEQ ID NO:154: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:154: Ile Thr Lys Gly Trp Lys GluVal 1 5 (2) INFORMATION FOR SEQ ID NO:155: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:155: Thr Glu Lys Leu Leu Lys Tyr Leu 1 5 (2)INFORMATION FOR SEQ ID NO:156: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:156: Lys Val Lys Arg Thr Lys Asp Glu 1 5 (2) INFORMATION FORSEQ ID NO:157: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157: Leu LysSer Lys Glu Val Trp Lys 1 5 (2) INFORMATION FOR SEQ ID NO:158: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158: Lys Ser Lys Glu ValTrp Lys Ala 1 5 (2) INFORMATION FOR SEQ ID NO:159: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:159: Ser Lys Glu Val Trp Lys 1 5(2) INFORMATION FOR SEQ ID NO:160: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:160: Arg Asn Leu Gly Lys Met Thr 1 5 (2) INFORMATION FOR SEQID NO:161: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B)TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161: Leu LeuLys Lys Ala Arg Ile 1 5 (2) INFORMATION FOR SEQ ID NO:162: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:162: Lys Lys Ala Arg Ile His ProPhe 1 5 (2) INFORMATION FOR SEQ ID NO:163: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:163: Tyr Lys Thr Gly His Gly Leu 1 5 (2)INFORMATION FOR SEQ ID NO:164: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:164: Glu Pro Thr Gly Lys Arg Phe Leu 1 5 (2) INFORMATION FORSEQ ID NO:165: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165: Leu ProMet Ile Trp Ala Gln Lys Thr Asn Thr Pro Ala 1 5 10 (2) INFORMATION FORSEQ ID NO:166: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166: Thr PheAla Gly Gly Val His Pro 1 5 (2) INFORMATION FOR SEQ ID NO:167: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167: Arg Glu Tyr Arg LysLys Met Asp 1 5 (2) INFORMATION FOR SEQ ID NO:168: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:168: Ile Gly Thr Phe Lys Ala PheAsp 1 5 (2) INFORMATION FOR SEQ ID NO:169: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:169: Thr Phe Lys Ala Phe Asp Lys His 1 5 (2)INFORMATION FOR SEQ ID NO:170: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:170: Asp Cys Asp Glu Phe Arg Lys Ile 1 5 (2) INFORMATION FORSEQ ID NO:171: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171: Cys AspGlu Phe Ala Lys Ile Lys 1 5 (2) INFORMATION FOR SEQ ID NO:172: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172: Asp Glu Phe Arg LysXaa Lys Pro 1 5 (2) INFORMATION FOR SEQ ID NO:173: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:173: Glu Phe Arg Lys Ile Lys ProLys 1 5 (2) INFORMATION FOR SEQ ID NO:174: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:174: Phe Arg Lys Xaa Lys Pro Lys Asn 1 5 (2)INFORMATION FOR SEQ ID NO:175: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:175: Arg Lys Ile Lys Pro Lys Asn Ala 1 5 (2) INFORMATION FORSEQ ID NO:176: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176: Lys IleLys Pro Lys Asn Ala Lys 1 5 (2) INFORMATION FOR SEQ ID NO:177: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177: Ile Lys Pro Lys AsnAla Lys Gln 1 5 (2) INFORMATION FOR SEQ ID NO:178: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:178: Lys Pro Lys Asn Ala Lys GlnPro 1 5 (2) INFORMATION FOR SEQ ID NO:179: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:179: Pro Lys Asn Ala Lys Gln Pro Glu 1 5 (2)INFORMATION FOR SEQ ID NO:180: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:180: Pro Gly Val Gly Arg Ala Ala Gly 1 5 (2) INFORMATION FORSEQ ID NO:181: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181: Val ArgGly Val Gly Gly Pro Ser 1 5 (2) INFORMATION FOR SEQ ID NO:182: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182: Gln Gln Val Met ThrPro Gln Gly 1 5 (2) INFORMATION FOR SEQ ID NO:183: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:183: Gln Val Met Thr Pro Gln GlyArg 1 5 (2) INFORMATION FOR SEQ ID NO:184: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:184: Val Met Thr Pro Gln Gly Arg Gly 1 5 (2)INFORMATION FOR SEQ ID NO:185: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:185: Met Thr Pro Gln Gly Asx Gly Thr 1 5 (2) INFORMATION FORSEQ ID NO:186: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186: Thr ProGln Gly Arg Gly Thr Val 1 5 (2) INFORMATION FOR SEQ ID NO:187: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187: Pro Gln Gly Arg GlyThr Val Ala 1 5 (2) INFORMATION FOR SEQ ID NO:188: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:188: Gln Gly Arg Gly Thr Val AlaAla 1 5 (2) INFORMATION FOR SEQ ID NO:189: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:189: Ala Pro Thr Gln Tyr Pro Pro Gly 1 5 (2)INFORMATION FOR SEQ ID NO:190: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:190: Pro Thr Gln Tyr Pro Pro Gly Arg 1 5 (2) INFORMATION FORSEQ ID NO:191: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191: Thr GlnTyr Pro Pro Gly Arg Gly 1 5 (2) INFORMATION FOR SEQ ID NO:192: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192: Gln Tyr Pro Pro GlyArg Gly Thr 1 5 (2) INFORMATION FOR SEQ ID NO:193: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:193: Tyr Pro Pro Gly Arg Gly ThrPro 1 5 (2) INFORMATION FOR SEQ ID NO:194: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:194: Pro Pro Gly Arg Gly Thr Pro Pro 1 5 (2)INFORMATION FOR SEQ ID NO:195: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:195: Pro Gly Arg Gly Thr Pro Pro Pro 1 5 (2) INFORMATION FORSEQ ID NO:196: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:196: Gly ArgGly Thr Pro Pro Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO:197: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:197: Arg Gly Thr Pro ProPro Pro Val 1 5 (2) INFORMATION FOR SEQ ID NO:198: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:198: Gly Thr Pro Pro Pro Pro ValGly 1 5 (2) INFORMATION FOR SEQ ID NO:199: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:199: Pro Pro Pro Pro Val Gly Arg Ala 1 5 (2)INFORMATION FOR SEQ ID NO:200: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:200: Ile Met Ala Pro Pro Pro Gly Met 1 5 (2) INFORMATION FORSEQ ID NO:201: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:201: Met AlaPro Pro Pro Gly Met Arg 1 5 (2) INFORMATION FOR SEQ ID NO:202: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:202: Ala Pro Pro Pro GlyMet Arg Pro 1 5 (2) INFORMATION FOR SEQ ID NO:203: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:203: Pro Pro Gly Met Arg Pro ProMet 1 5 (2) INFORMATION FOR SEQ ID NO:204: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:204: Pro Pro Ala Arg Gly Thr Pro Ile 1 5 (2)INFORMATION FOR SEQ ID NO:205: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:205: Ile Gly Met Pro Pro Pro Gly Met 1 5 (2) INFORMATION FORSEQ ID NO:206: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:206: Gly MetPro Pro Pro Gly Met Asx 1 5 (2) INFORMATION FOR SEQ ID NO:207: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:207: Pro Pro Pro Gly MetAsx 1 5 (2) INFORMATION FOR SEQ ID NO:208: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:208: Met Pro Pro Pro Gly Met Arg Pro 1 5 (2)INFORMATION FOR SEQ ID NO:209: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:209: Pro Pro Gly Met Arg Pro Pro Pro 1 5 (2) INFORMATION FORSEQ ID NO:210: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:210: Met ArgPro Pro Pro Pro Gly Ile 1 5 (2) INFORMATION FOR SEQ ID NO:211: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:211: Arg Pro Pro Pro ProGly Ile Arg 1 5 (2) INFORMATION FOR SEQ ID NO:212: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:212: Pro Pro Pro Gly Ile Arg 1 5(2) INFORMATION FOR SEQ ID NO:213: (i) SEQUENCE CHARACTERISTICS: (A)LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:213: Pro Pro Pro Pro Gly Ile Arg Gly 1 5 (2) INFORMATION FORSEQ ID NO:214: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids(B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii)MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:214: Pro ProGly Ile Arg Gly Pro Pro 1 5 (2) INFORMATION FOR SEQ ID NO:215: (i)SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE:peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:215: Arg Gly Pro Pro ProPro Gly Met 1 5 (2) INFORMATION FOR SEQ ID NO:216: (i) SEQUENCECHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C)STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:216: Gly Pro Pro Pro Pro Gly MetArg 1 5 (2) INFORMATION FOR SEQ ID NO:217: (i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCEDESCRIPTION: SEQ ID NO:217: Pro Pro Pro Pro Gly Met Arg Pro 1 5 (2)INFORMATION FOR SEQ ID NO:218: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH:8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D)TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:218: Pro Pro Gly Met Arg Pro Pro Arg 1 5

I claim:
 1. A linear epitope for a human autoantibody selected from thegroup of peptides of less than forty amino acids comprising an aminoacid sequence capable of binding to an autoantibody consisting of theLa/SSB epitopes: QVLNIQMRRTLHKAFKGS (SEQ ID NO:19), NIQMRRTLHKAFK (SEQID NO: 136), RTLHKAFK (SEQ ID NO: 137), ICHQIEYYFGDFNLPRDKFLK (SEQ IDNO:20), YFGDFNLP (SEQ ID NO:138), WVPLEIMIKFNR (SEQ ID NO: 21), VPLEIMIK(SEQ ID NO:139), KTKIRRSPSKPL (SEQ ID NO: 22), KIRRSPSK (SEQ ID NO:140), NRLNRLTTDFNVIVE (SEQ ID NO:23), NRLNRLTT (SEQ ID NO: 118),GEIKWIDFVRGAK (SEQ ID NO: 24), KWIDFVRGAK (SEQ ID NO: 103), IDFVRGAK(SEQ ID NO:104), SLNKWKSKGRRFKGKGKGNK (SEQ ID NO: 25), KSKGRRFK (SEQ IDNO: 105), GNLQLRNKEVTW (SEQ ID NO:26), LRNKEVTW (SEQ ID NO:106),IFVVFDSIE (SEQ ID NO:27), FVVFDSIE (SEQ ID NO:107), KETDLLILFKDDYFA (SEQID NO: 28), ILFKDDYF (SEQ ID NO: 108), YKNDVKNRSVYIKGFPT (SEQ ID NO:29),SVYIKGFP (SEQ ID NO: 109), TDFNVIVE (SEQ ID NO: 110), DFNVIVEA (SEQ IDNO:111), EGIILFKEKAK (SEQ ID NO:31), EGIILFKE (SEQ ID NO:112),KVQFQGKKTKFASD (SEQ ID NO:32), KKTKFASD (SEQ ID NO:113), REDLHILF (SEQID NO:33), CLLKFSGD (SEQ ID NO:34), TGPVKRAR (SEQ ID NO:35), KVEAKLRAKQ(SEQ ID NO:36), EAKLRAKQ (SEQ ID NO:114).
 2. The epitope of claim 1consisting of between four and twenty five amino acids.
 3. The epitopeof claim 2 reactive with anti-La/SSB polyclonal antibodies.
 4. Theepitopes of claim 1 in combination with a pharmaceutical carrier foradministration to a patient.
 5. The epitopes of claim 4 in an effectiveconcentration for administration to a patient to neutralize circulatingautoantibody.
 6. The epitopes of claim 4 further comprising apharmaceutical carrier for administration to a patient, wherein thecarrier and concentration of sequences elicit an immune response whenadministered to a host.
 7. The epitopes of claim 1 labelled with acompound selected from the group consisting of dyes, fluorescent labels,chemiluminescent labels, enzymes, and radioactive labels.
 8. Theepitopes of claim 1 immobilized onto a substrate.